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Neuromodulator signaling and activity in the C. elegans egg-laying circuit

Award Number: R01NS086932
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Neuromodulator signaling and activity in the C. elegans egg-laying circuit - Project Summary/Abstract The long-term goal of this project is to delineate at an unprecedented level of precision how all the neurotransmitter and neuropeptide signaling events within a model neural circuit together produce its dynamic pattern of activity. Neural circuits are a basic unit of brain function and altered signaling within neural circuits can disrupt circuit function to produce human brain diseases. To date, our understanding of such diseases remains vague because we understand only a few individual features within each of the many different neural circuits that have been studied. Therefore, our approach is to analyze all the signaling events within one simple neural circuit, anticipating that this will yield new insights into how neural circuits in general work. This approach is inspired by past successes in other areas of biology in which deep analysis of a simple model in a genetically tractable organism (e.g. the lac operon in E. coli) led to conceptual breakthroughs that generalized to human biology. Thus, we are intensely studying the simple egg-laying behavior circuit of C. elegans, in which we have developed a powerful combination of genetic, optogenetic, chemogenetic, and Ca2+ imaging approaches that provide unprecedented mechanistic insights into circuit function. This circuit alternates between ~20 minute inactive states when eggs collect in the uterus and ~2.5 minute active states when eggs are laid. In past work, we studied how the circuit turns on, and we now turn our focus to understanding how the circuit turns off. We identified specific neurotransmitters and neuropeptides that signal through the heterotrimeric G protein Gαo to turn off the circuit by antagonizing the Gαq signaling that turns the circuit on. Aim 1 uses biochemistry, genetics, Ca2+ and fluorescent reporter imaging, and electrophysiology to test our hypothesis that Gαo directly activates a G protein GTPase activator to terminate Gαq/Rho signaling and a diacylglycerol kinase to terminate Gαq/PLCBb signaling, thus inhibiting neuron and muscle electrical excitability. Aim 2 uses genetics, Ca2+ imaging, and electron microscopy to define structures and functions of the remaining uncharacterized components of the circuit, including 1) PVW neurons, which we found branch over the egg-laying muscles and regulate egg laying; and 2) gap junctions between these muscle cells. Aim 3 studies how mechanosensory feedback inhibits the circuit after eggs are successfully laid. We discovered that specific neurons detect egg release, and that egg- laying muscles appear to detect when fewer unlaid eggs remain in the uterus. We will use genetics, Ca2+ imaging, and physiological approaches to study the mechanisms of this mechanosensory feedback inhibition of circuit activity. The molecular, cellular, and circuit-level mechanisms we are defining that control activity of the C. elegans egg-laying circuit are likely conserved and will inform our understanding of neural circuits in general. Aim 1. We will determine how Gαo antagonizes Gαq signaling to regulate neuron and muscle activity. Aim 2. We will define the remaining components of the egg-laying circuit and their connectivity. Aim 3. We will determine how mechanosensory feedback of egg laying turns the circuit off.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $603,519 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	2/26/2026	NON-COMPETING CONTINUATION	$603,519
														Subtotal = $603,519

Issue Date FY: 2025 ( Subtotal = $510,883 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/9/2025	NON-COMPETING CONTINUATION	$514,436
2025	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	2/21/2025	NON-COMPETING CONTINUATION	$0
2025	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	5/7/2025	NON-COMPETING CONTINUATION	-$3,553
														Subtotal = $510,883

Issue Date FY: 2024 ( Subtotal = $616,225 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	1/23/2024	COMPETING CONTINUATION	$616,225
2024	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $616,225

Issue Date FY: 2022 ( Subtotal = $635,727 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	3/31/2022	NON-COMPETING CONTINUATION	$437,961
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	4/6/2022	SUPPLEMENT FOR EXPANSION	$71,942
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	1/5/2022	SUPPLEMENT FOR EXPANSION	$40,097
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	8	4/7/2022	SUPPLEMENT FOR EXPANSION	$85,727
														Subtotal = $635,727

Issue Date FY: 2021 ( Subtotal = $507,506 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	6/16/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/26/2021	NON-COMPETING CONTINUATION	$443,664
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/10/2021	SUPPLEMENT FOR EXPANSION	$63,842
														Subtotal = $507,506

Issue Date FY: 2020 ( Subtotal = $413,750 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	4/17/2020	NON-COMPETING CONTINUATION	$413,750
2020	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/9/2020	COMPETING CONTINUATION	$7,040
2020	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/9/2020	NON-COMPETING CONTINUATION	-$7,040
														Subtotal = $413,750

Issue Date FY: 2019 ( Subtotal = $452,035 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/31/2019	COMPETING CONTINUATION	$452,035
2019	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/29/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $452,035

Issue Date FY: 2017 ( Subtotal = $364,219 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/14/2017	NON-COMPETING CONTINUATION	$364,219
														Subtotal = $364,219

Issue Date FY: 2016 ( Subtotal = $363,628 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/10/2016	NON-COMPETING CONTINUATION	$363,628
														Subtotal = $363,628

Issue Date FY: 2015 ( Subtotal = $363,645 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/11/2015	NON-COMPETING CONTINUATION	$363,645
														Subtotal = $363,645

Issue Date FY: 2014 ( Subtotal = $335,125 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/21/2014	NEW	$335,125
														Subtotal = $335,125

Grand Total All Awards = $5,166,262

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Neuromodulator signaling and activity in the C. elegans egg-laying circuit

Award Number: R01NS086932

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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